EP1028725A1

EP1028725A1 - Application of vasopressin antagonists for treating disturbances or illnesses of the inner ear

Info

Publication number: EP1028725A1
Application number: EP98962320A
Authority: EP
Inventors: Hans Peter Zenner; J. Peter Ruppersberg; Hubert LÖWENHEIM
Original assignee: Otogene AG
Current assignee: ZENNER, HANS PETER, PROF. DR.
Priority date: 1997-11-05
Filing date: 1998-11-04
Publication date: 2000-08-23
Anticipated expiration: 2018-11-04
Also published as: AU1753699A; DE19748763A1; WO1999024051A3; ATE259230T1; WO1999024051A2; EP1028725B1; CA2309117A1; JP2001522807A; DE59810761D1; ES2218875T3; BR9813957A

Abstract

The invention relates to the application of at least one vasopressin receptor antagonist or mixture of such antagonists in order to treat disturbances or illnesses of the inner ear. These disturbances/illnesses can be connected to at least one of the following symptoms: vertigo, impairment of hearing or tinnitus. The symptoms can especially relate to those of so-called Ménièr's disease. According to the invention, especially vasopressin V2 receptor antagonists can be applied, whereby the antagonists can be peptidic or non-peptidic substances.

Description

Description:

USE OF VASOPRESSIN ANTAGONISTS FOR THE TREATMENT OF INNER EAR DISORDERS OR DISEASES

The invention relates to the use of at least one vasopressin receptor antagonist or mixtures thereof.

Vasopressin (VP) is known to be a peptide hormone from the pituitary lobe. Because of its antidiuretic effect, it is also known as antidiuretin or antidiuretic hormone (ADH). The form of the hormone found in humans and many mammals is a cyclic peptide of nine amino acids with a disulfide bridge, in which arginine is located in the 8-position. Accordingly, this form is also called arginine vasopressin (AVP).

As already mentioned, the influence of vasopressin in water diuresis in the kidneys, namely its antidiuretic effect, is particularly important physiologically. Vasopressin makes the so-called collecting tubes in the kidney permeable to water and in this way enables the reabsorption of water in the kidneys and thus the concentration of urine. The epithelia of the collecting tubes react to the presence of vasopressin. The hormone introduced from the blood side of the epithelial cells binds to specific receptors and stimulates the increase in water permeability via intracellular cAMP (second messenger cyclic adenosine 3 ', 5-monophosphate). The underlying mechanism can be thought of as forming water channel-forming glycoproteins in the so-called main cells. In the case of the main cells of the collecting tube of the kidney, this glycoprotein is the aquaporin-2 which has so far only been found there. This is first stored in small vesicles inside the cell and, when vasopressin is present at the receptor, is built into the apical cell membrane. Thereby the hormone-regulated water entry into the cell is made possible.

Vasopressin receptors that mediate cAMP-dependent water channel regulation in the epithelial cells of the collecting tubes in the kidney are referred to as V ₂ receptors.

Vasopressin therefore has a water-reabsorbing effect in the epithelial cells of the kidney collecting tubes. This can be inhibited by vasopressin receptor antagonists.

Accordingly, these antagonists in the kidney counteract the action of vasopressin and thus increase the flow of urine while diluting the urine.

Vasopressin receptor antagonists are already known in connection with the antidiuretic effect of vasopressin. These can be peptide or non-peptide substances. With regard to the peptide substances, reference is made to the publications by M. Manning and W.H. Sawyer in J. Lab. Clin. Med. 114, 617-632 (1989) and F.A. Laszlo et al. in Pharmacol. Rev., 43, 73-108 (1991). Representations of non-peptide substances can be found in Y. Yamamura et al. in Br. J. Pharmacol. 105: 787-791 (1992) and C. Serradeil-Le Gal et al. in J. Clin. Invest., 98 (12), 2729-2738 (1996). All of these substances have been studied and used in relation to the antidiuretic effect of vasopressin.

Previous findings and studies on disorders or diseases of the inner ear cannot, however, be reconciled with the findings described above about the antidiuretic effect of vasopressin and the inhibition of this effect by antagonists. This applies in particular to the so-called. Endoly phhydrops in the inner ear, in which there is a liquid excess of the endolymph in the endolymph space of the inner ear. This endolymph hydrops can with a Overproduction or a drainage disorder of the endolymph, especially in the so-called endolymphatic sac (Saccus endolymphatic), are related. Although the existence of vasopressin in the inner ear has been proven, the use of vasopressin antagonists cannot be considered based on the previous knowledge of the water reabsorbing effect of vasopressin. With an increased volume of fluid in the inner ear, which can trigger the symptoms of the disease, the known effect of vasopressin would be desirable. This effect would be inhibited by the use of the antagonist.

It has now surprisingly been found that in the inner ear, in particular in the epithelium of cells which enclose the endolymph, the water permeability can be established or improved by using vasopressin receptor antagonists. This unexpected, opposite effect of the antagonist compared to its effect in the kidney enables the use of such substances or their mixtures for the treatment of disorders or diseases of the inner ear.

Accordingly, the object according to the invention of making active substances for the treatment of disorders or diseases of the inner ear accessible is achieved by the use according to claim 1. Preferred embodiments are mentioned in the dependent claims 2 to 16. The content of all these claims is hereby incorporated by reference into the content of the description.

According to the invention, at least one vasopressin receptor antagonist or mixtures thereof can be used for the treatment of disorders or diseases of the inner ear. In particular, the use for the production of a corresponding medicament or a corresponding pharmaceutical composition is also included, the antagonist optionally can also be used in the form of one of its pharmaceutically acceptable salts and, if appropriate, in a mixture with a pharmaceutically acceptable carrier or diluent.

The receptor antagonists used according to the invention are preferably those which interact with one of the V ₂ receptors mentioned above. According to current knowledge, these V ₂ receptors are those which are primarily related to the antidiuretic effect of vasopressin.

The disturbance or disease of the inner ear that is to be treated with the use according to the invention is preferably associated with at least one of the symptoms dizziness (balance problems), hearing loss, tinnitus (ringing in the ears) or a feeling of pressure in the ear. The symptoms of dizziness, hearing loss or tinnitus are particularly noteworthy. In the use according to the invention, one of the symptoms mentioned can occur alone, but any combination of two or three symptoms or the occurrence of all three or four symptoms in inner ear disorders is typical.

The symptom of hearing loss can occur in particular as so-called low-frequency hearing loss, and preferably as fluctuating low-frequency hearing loss.

According to current knowledge, the disorders or diseases of the inner ear that can be treated by the use according to the invention can frequently and preferably be associated with a so-called hydrops, in particular an endolymph hydrops. As is known, a hydrops is a fluid accumulation or a fluid build-up in the body, in particular in cavities present there. With the endolymph hydrops already mentioned above it is a liquid excess of the so-called endolymph. This excess fluid can be attributed to an overproduction or an outflow disorder of the endolymph, especially in the so-called Saccus endoly phaticus. The endolymph hydrops result in an increased pressure and an increase in volume of the space in which the endolymph is located. Since this relates to a change in the deflection of the sensory hairs, which are responsible for hearing and the sense of balance, the symptoms mentioned, in particular dizziness, hearing loss and tinnitus, can be explained with an endolymph hydrops.

Of the treatable disorders or diseases, the so-called Meniere's disease, which is usually associated with the symptoms of dizziness, deafness and tinnitus (ear noise), should be mentioned in particular. Various influences can be considered as triggers for Meniere's disease, such as stress, infections, tumors, immunological or neurogenic disorders, etc. Meniere's disease is to be understood here as a type of collective name for disorders in which the corresponding symptoms differ in their expression may occur, such as vestibular Meniere's disease. The so-called Lermoyez disease can also be mentioned as a possible application. Furthermore, disorders / diseases of the inner ear that are manifested in low-frequency hearing loss can preferably be treated. Corresponding low-frequency deafness often occurs after inflammatory diseases, such as creeping otitis media or syphilis, with toxic influences or as

"delayed hydrops syndrome ¹¹ or also as a result of venous congestion (stasis) or vascular disorders of the inner ear. All disorders / diseases of the inner ear which, in addition to those already mentioned, can be linked to endolymph drainage disorders in the endolymphatic sac, are possibly particularly suitable for use of the present invention.

According to the invention, known or also further new vasopressin receptor antagonists, in particular vasopressin V ₂ receptor antagonists, can be used. Such substances, like the vasopressin itself, can be peptide compounds which, like the vasopressin, interact with the receptor. Such peptide compounds are disclosed, for example, in the previously mentioned publication by M. Manning and WH Sawyer. These can in particular be comparatively easily accessible linear peptides, the peptide propionyl-D-Tyr (Et) - Phe-Val-Asn-Abu-Pro-Arg-Arg-NH _{2 being} used in particular. The building blocks of the peptide sequence shown have the usual meaning in biochemistry, with Abu being βfe-L-aminobutyric acid. A selection of linear peptide compounds that can be used in principle as vasopressin receptor antagonists, including the particularly highlighted compound, are described in the publication by M. Manning et al. in Int. J. Peptide Protein Res. 32, 455-467 (1988). The compound reproduced above with its peptide sequence is available from BACHEM Feinchemischem AG, Bubendorf, Switzerland, under product no. H-9400 sold.

In principle, non-peptide receptor antagonists for vasopressin can also be used, which are preferably non-peptide organic substances, which in turn are preferably produced synthetically. The previously known organic substances can be

Benzazepine derivatives act as described, for example, in EP-Al-514667. Particularly noteworthy is that in the publication by Y. Yamamura et al. Substance 5-dimethylamino-1- {4-4 described in Br. J. Pharmacol., 105, 787-791 (1992) under the name OPC-31260. (2methylbenzoylamino) benzoyl} -2, 3,4,5-tetrahydro-1H-benzazepine. In this respect, the content of this publication is made the content of this description. Also suitable as possible non-peptidic organic substances are indole derivatives, such as those which can be found in principle in WO 93/15051, WO 95/18105 and EP-Al-645375. The N-sulfonyl-2-θxoindole derivative is, in particular, that described in J. Clin. Invest. 98 (12), 2729-2738 (1996) under the designation SR 121463A described 1- [4- (N-tert-butylcarbamoyl) -2-methoxybenzenesulfonyl] -5-ethoxy-3-spiro- [4- (2-morpholinoethoxy) cyclohexane ] to call indol-2- one, fumarate.

It is further preferred according to the invention that the receptor antagonist can be administered orally and / or intravenously. In particular, an oral route of administration, such as that which non-peptidic receptor antagonists have in comparison to the peptidic receptor antagonists for vasopressin, is particularly favorable, since this considerably simplifies the administration to a patient.

The use of the vasopressin receptor antagonists according to the invention can in principle be carried out in any manner, the chosen administration form also being adapted to the age, gender or other characteristics of the patient, the severity of the disorders / diseases and other parameters. When used for oral administration, for example, tablets, pills, solutions, suspensions, emulsions, granules or capsules can be produced in principle. Conventional pharmaceutical carriers, diluents or conventional additives can be present here. For intravenous administration, the antagonists can be provided alone or together with conventional auxiliary liquids such as glucose, amino acid solutions and the like. Also a provision for intramuscular, subcutaneous or intraperitoneal administration may be possible. Administration in the form of suppositories should also be considered.

The dosage can also be freely selected depending on the clinical picture and the patient's conditioning. Usually amounts of 0.1 to 50 mg / kg body weight and per day can be provided. The receptor antagonist for vasopressin is usually contained in an amount of about 10 to 1,000 mg per unit. In a preparation intended for administration or a corresponding medicament, the receptor antagonist for the vasopressin is preferably contained in an amount of 1 to 75% by weight. Within this range, values between 5 and 50% by weight, in particular 5 to 25% by weight, are preferred.

A preparation or a corresponding medicament produced according to the invention is generally used systemically, the oral route already mentioned being preferred. A local application in

Direction towards the inner ear may be possible if, for example, an operation can be used to access the inner ear. Thus, it is possible to lay a drainage after exposure of the endolympathic sac, in which case the vasopressin receptor antagonist, for example with the aid of a pump, is guided directly to the site of action of a corresponding inner ear disorder / disease.

Furthermore, the invention comprises a method for the treatment of disorders or diseases of the inner ear, which is characterized in that at least one vasopressin receptor antagonist or a mixture thereof is administered in a suitable amount suitable for the body of the animal or human being to be treated. For the individual features of such a procedure, reference is made to the previous text

Description expressly referred to, in particular the treatable disorders / diseases and the receptor antagonists that can be used are defined.

Finally, the invention comprises a pharmaceutical composition or a medicament for the treatment of disorders or diseases of the inner ear which contains at least one vasopressin receptor antagonist or mixtures thereof. For the individual features of such a composition or of such a medicament, reference is also made to the corresponding previous text of the description.

The described features and further features of the invention result from the following description of preferred embodiments in conjunction with the subclaims and the figures. The individual features can be implemented individually or in combination with one another.

The pictures show:

Fig. 1 the position of the Reissner membrane in the cochlea in adult guinea pigs a without vasopressin addition b with chronic vasopressin addition c with acute vasopressin addition d with acute vasopressin addition (enlarged detail)

Fig. 2 Expression of a V ₂ receptor and b aquaporin-2 in the epithelium of the endophilic sac in the inner ear of the rat.

Fig. 3 Autoradiography of the human endolymphatic sack c in the epithelium with ¹²⁵ I-vasopressin d control test in the presence of unlabelled vasopressin.

Fig. 4 Organotypic culture of the rat endolymphatic sack a Overview image b Infrared light microscopy c SEM image d SEM image (higher magnification).

Fig. 5 membrane turnover in the culture according to Fig. 4 a FITC-dextran-labeled endosomes in the absence of vasopressin b FITC-dextran-labeled endosomes in the presence of vasopressin c SEM uptake in the case of ad SEM uptake in the case of FITC- Dextran-labeled endosomes in the presence of forskolin f FITC-dextran-labeled endosomes in the presence of cholera toxin g FITC-dextran-labeled endosomes in the presence of vasopressin and V ₂ - receptor antagonist H-9400.

Experiment 1

Guinea pigs with a normal Preyer reflex weighing between 300 and 500 g were used for the investigation. To study the acute effects of vasopressin, Pitressin © (arginine-vasopressin AVP) from Sankyo, Japan, was injected intraperitoneally (0.2 units / g). The guinea pigs were sacrificed for histology two hours after the injection. For the chronic experiments, 0.5 units / g of the vasopressin was applied once for 60 days administered subcutaneously per day. 20 animals were used for the study of the acute effect and 10 animals for the study of the chronic effect. For comparison, 0.2 ml of physiological saline solution were injected intraperitoneally into 10 control animals. The cochleae of all test animals were embedded in celloidin and the central modiolar sections were stained with haematoxylin / eosin (HE). Due to the deflection of the Reissner membrane, the presence of an endolymphatic hydrop was determined.

The results of Experiment 1 are shown in Fig. 1.

Fig. La shows that the Reissner membrane, for example marked with an arrow, is not deflected in the control animals (n = 10) and accordingly there is no endolymph hydrops.

According to Fig. 1b, a strong endolymphatic hydrops can be demonstrated in a test animal with chronic administration of vasopressin (n = 10) due to the strong displacement of the Reissner membrane. In the helix turn, which corresponds to the one marked with the arrow in Fig. La, the Reissner membrane even touches the bony partition between turns 3 and 4. Of the test animals chronically treated with vasopressin, four out of ten showed severe hydrops as shown in Fig. Lb and another three showed mild to moderate hydrops.

Fig. Lc shows a mild to moderate endolymph hydrops in a test animal after a single injection of vasopressin, ie acute treatment. At n = 20, eight of these twenty test animals showed such slight to moderate hydrops. Fig. Ld shows the same case as Fig. Lc, but at a higher magnification. In contrast to Fig. Lb, no contact with the bony partition is detectable, but significant protuberances of the Reissner membrane. Experiment 1 and the corresponding Fig. 1 thus show that increased plasma values of vasopressin can cause an endolymph hydrops.

Experiment 2

PCR (polymerase chain reaction) experiments were carried out with the primers AQP2s, AQP2as, V2s and V2as. The primers had the following nucleotide sequences

AQP2S GAT CGC CGT GGC CTT TGG TCT

AQP2as AGG GAG CGG GCT GGA TTC AT

V2s AGT GCT GGG GGC CCT AAT ACG

V2as CAA ATC GGG CCC AGC AAT CAA ACA

The cDNAs of aquaporin-2 and the V ₂ receptor were amplified using the primer pairs AQP2s / AQP2as and V2s / V2as, respectively. The PCR was carried out in a total volume of 50 μl, the 5 μl of the reverse transcriptase, each 0.8 μM of the primers, each 200 μM of the dNTPs, an incubation buffer (containing 1.5 mM MgCl ₂ , from Pharmacia) and 1 , 25 U

Taq polymerase (also from Pharmacia) contained. After a denaturation step at 94 ° C of 7.5 min at the beginning, there were 40 cycles of 50 sec at 94 ° C, 50 sec at 55 ° C and 50 sec at 72 ° C and a ten minute step at 72 ° C at the end. The expected lengths of the products were 428 bp and 419 bp, respectively. The PCR products were processed in the usual way and detected by subcloning and sequencing.

As can be seen from Fig. 2, both V ₂ receptor and aquaporin-2 are strongly expressed in the epithelium of the endolymphatic sack, while such detection is not possible in other epithelium of the inner ear, which are also in contact with the endolymph.

According to Fig. 2a, the V receptor could be seen in the inner ear of the rat both on postnatal day 4 (p4) and in the adult rat (ad) can be demonstrated. Very weak bands were obtained in the endolymphatic sac on postnatal day 1 (pl), in the stria vascularis (StV), in the vestibular organ (V) or in the Reissner membrane (RM). According to Fig. 2b, expression of aquaporin-2 was most evident in the adult endolymphatic sac, clearly detectable on postnatal day 4, but no expression in the stria vascularis, vestibular organ or in the Reissner membrane could be detected.

Experiment 3

Human endolymphatic saccus was obtained from six autopsies and two operated patients with the consent of relatives or patients. Frozen sections (20 μm) were cut on a cryostat at -16 ° C

Gelatin-coated platelets applied and stored under vacuum at 4 ° C. overnight. The tissue sections were incubated with ¹²⁵ I-arginine vasopressin overnight at 4 ° C. in the absence (total binding) or presence of 10 μM of unlabelled arginine vasopressin (non-specific binding) in ice-cold 10 mM Tris-HCl buffer (pH 7 , 4) containing 10 mg MgCl ₂ , 0.5 mg / ml bacitracin and 0.1% bovine serum albumin. The radiolabeled sections were coated with NTB-2 nuclear emulsion (Eastman Kodak) and prepared for light microscopic autoradiography. The coated platelets were stored in the dark at 4 ° C for three to eight days. After developing and fixing, the platelets were stained with haematoxylin / eosin.

Fig. 3 shows the results of experiment 3. The specific binding of radioactive vasopressin in the human endolymphatic sac can be seen. The dots in Fig. 3c show the binding of the vasopressin in the epithelium of the endolymphatic sac, while according to Fig. 3d the same treatment in the presence of unlabelled vasopressin precludes unspecific vasopressin binding in the saccus.

Experiment 4 Rats were anesthetized on postnatal day 4 with sodium pentobarbital (0.4 mg / gr body weight) and then decapitated. The temporal bones were removed immediately and transferred to cold (4 ° C) HEPES buffered saline with Hank's saline solution (HHBSS). The complete endolymphatic sack was separated from the temporal bone, opened at the corner of the distal part of the saccus, and placed flat in a culture plate coated with 20 µl Cell Tek from Becton Dickinson Labware, USA, diluted 1: 5, and with 300 µl Culture medium covered. The culture medium consisted of minimum essential medium with D-valine to suppress the growth of fibroblasts and which was supplemented with 10% calf fetus serum, 10 mM HEPES, 100 IU / ml penicillin and 2 mM glutamine. The cultures were kept in a 5% carbon dioxide atmosphere at 37 ° C for up to 5 days. The morphology of the culture was observed by infrared light microscopy. A detailed surface morphology of the epithelia was obtained by SEM (Scanning Electron Microscopy). The coverslips of the explants were fixed in 2.5% glutaraldehyde, 0.1 M sodium cocodylate buffer for 120 minutes, post-fixed in 1% osmium tetroxide for 60 minutes, washed, dried, gold-coated by standard procedure and examined in a Hitachi 500-SEM.

Fig. 4 shows the results of Experiment 4

Fig. 4a shows an overview of an endolymphatic saccus after four days in culture, proximal (PSP), intermediate (ISP) and distal (DSP) parts of the saccus being shown. The structural analysis of the culture epithelium of the Saccus endolymphaticus shown in Fig. 4b and 4c shows a clear similarity to the native organ with mito- Chondria and ribosome-rich cells of typical shape. The image of the infrared light microscope shows individual cells in the intermediate part, whereby two cell types can be differentiated according to shape and surface morphology. The polygonal shaped cells, which correspond to the ribosome-rich cells (RRC), have a flat surface, while the round cells, which correspond to the mitochondrial-rich cells (MRC), have numerous microvilli protruding into the lumen. This can also be clearly seen from the SEM image according to Fig. 4c. The higher magnification according to Fig. 4d also clearly shows the clathrin-coated holes in the luminal cell membrane in the RRC cells of the endolymphatic sac (see arrow).

Experiment 5

In a culture according to Experiment 4, after 12 hours of culture, the endolymphatic sack in HHBSS (pH 7.3) containing 1.0 mg / ml fluorescein isothiocyanate (FITC) dextran (from Sigma, Germany) was at 37 ° C for incubated for about 10 min. The endolymphatic sack was then washed with HHBSS and fixed with 4% paraformaldehyde in PBS for 20 min. Fluorescence and interference contrast images were taken through an epifluorescence microscope (Olympus, AX-70, Germany) with a standard FITC filter set (excitation: 485 + 20 nm; emission:> 510 nm) and superimposed on one another to include the non-fluorescent cells visualize and discriminate the cells rich in mitochondria and ribosomes. Subsequently, vasopressin, forskolin, cholera toxin (all from Sigma, Germany) or the V ₂ receptor antagonist H-9400 (BACHEM, Switzerland) were added to the solutions together with FITC-dextran, in the amounts described below.

Figure 5 shows the results of Experiment 5. Fig. 5a shows the endosomes represented by the FITC-dextran, which is observed in the culture of the endolymphatic sack in the RRC and MRC in the absence of other substances, ie in a control experiment (n = 120). When 1 nM vasopressin (n = 84) is added, membrane conversion in RRC is inhibited, ie no labeled endosomes are visible in RRC. Labeled endosomes are still observed in MRC. This means that in the endolymphatic sac the vasopressin (in contrast to the situation in the epithelium of the collecting tube of the kidney) inhibits the absorption of FITC-dextran in ribosome-rich cells (RRC). Thus, in the example according to FIG. 5b, 10.5 + 2.1 of 118.5 + 2.8 cells show FITC dextran uptake (n = 20), compared with an untreated sample according to the example in FIG. 5a, in which 90.5 ± 2.5 of 116.5 ± 2.4 cells showed FITC dextran uptake (at n = 20).

The inhibitory effect of vasopressin on membrane turnover is also demonstrated by the disappearance of the clathrin-coated holes (pits) from the apical cell surface of the ribosome-rich cells according to the SEM images of FIGS. 5c and 5d. Thus, under control conditions, RRC showed numerous coated holes (see arrow in Fig. 5c), which were already shown in Fig. 4d at higher magnifications. The crossbar in Fig. 5d represents a length of 1 μ. According to Fig. 5d, almost no holes are visible after treatment with 1 mM vasopressin, which suggests the internalization of clathrin, presumably clustered with aquaporin-2.

According to Fig. 5e and 5f, as in the case of vasopressin, almost no endosomes were also detected when using 50 μM forskolin (n = 48) or 0.1 nM cholera toxin (n = 36).

Just as surprising as the result of the experiment shown in Figure 5b is the test result according to Fig. 5g, in which a simultaneous application of 10 nM vasopressin and 10 nM V ₂ receptor antagonist H-9400 abolishes the vasopressin effect according to Fig. 5b. The FITC-dextran-filled endosomes are still present (test number n = 30).

The described FITC-dextran experiments take advantage of the known fact that the membrane conversion can be represented by FITC-dextran and correlates with the water transport through the membrane. A high membrane conversion proven by FITC-Dextran suggests a high water transport. Since the epithelium of the endolymphatic sack consists almost exclusively of RRC and MRC cells, the detection carried out according to experiment 5 is meaningful for the endolymphatic sack as a whole and for the supplying duct. The results are also in agreement with the fact that vasopressin is active on the RRC cells and therefore the effect of vasopressin or vasopressin antagonist is detectable there. The MRC cells are not active with vasopressin and, accordingly, have no effect according to experiment 5.

Due to the fact that the peptide antagonist H-9400 used is a comparatively selective V receptor antagonist, the test results are a strong indication that the vasopressin receptor on the endolymphatic sac of the inner ear is of the V ₂ type. Surprisingly, however, the vasopressin in the inner ear obviously has the opposite effect as in the epithelial cells of the collecting tube of the kidney. This also explains the surprising result that the vasopressin receptor antagonist increases membrane turnover and thus water transport, in contrast to the known effects in the kidney, and thus a water-absorbing effect is achieved by using the antagonist. This systematic finding makes the use of the vasopressin receptor antagonists according to the invention for the treatment of diseases or disorders of the inner ear, especially those associated with a hydrops such as an endolymph hydrops. An effect of the antagonist associated with a decrease in volume on the luminal side leads to a decrease in pressure and volume in the inner ear, in contrast to the known effect in the kidney, if there is excess pressure or if the volume is too large. These are suitable for alleviating or eliminating the symptoms, in particular dizziness, hearing loss and tinnitus. The use according to the invention can also have a prophylactic effect in the case of such inner ear disorders.

Claims

claims

1. Use of at least one vasopressin receptor antagonist or mixtures of such antagonists for the treatment of disorders or diseases of the inner ear.

2. Use according to claim 1, characterized in that the receptor antagonist is a vasopressin-V receptor antagonist.

Use according to claim 1 or claim 2, characterized in that the disturbance or disease of the inner ear is associated with at least one of the symptoms of dizziness, hearing loss or tinnitus.

4. Use according to claim 3, characterized in that the hearing loss is a low-frequency hearing loss.

5. Use according to one of the preceding claims, characterized in that the disturbance or disease of the inner ear is related to a hydrops, in particular an endolymph hydrops.

6. Use according to any one of the preceding claims, characterized in that the disorder or disease of the inner ear is Meniere's disease.

7. Use according to one of the preceding claims, characterized in that the receptor antagonist is a peptide compound.

8. Use according to claim 7, characterized in that the peptide compound is a linear peptide, in particular propionyl-D-Tyr (Et) -Phe-Val-Asn-Abu-Pro-Arg-Arg-NH.

9. Use according to one of claims 1 to 6, characterized in that the receptor antagonist is a non-peptidic, preferably non-peptidic organic substance.

10. Use according to claim 9, characterized in that the organic substance is a benzazepine derivative.

11. Use according to claim 10, characterized in that the benzazepine derivative is 5-dimethylamino-l- {4- (2methyl-benzoyla ino) benzoyl} -2, 3,4,5-tetrahydro-1H-benzazepine.

12. Use according to claim 9, characterized in that the organic substance is an indole derivative.

13. Use according to claim 12, characterized in that the indole derivative l- [4- (Ntert-butylcarbamoyl) -2-methoxy-benzenesulfonyl] -5-ethoxy-3-spiro- [4- (2-morpholino-ethoxy ) cyc1ohexane] indo1-2-one, fu arat is.

14. Use according to one of the preceding claims, characterized in that the receptor antagonist can be administered orally and / or intravenously, in particular orally.

15. Use according to one of the preceding claims, characterized in that the receptor antagonist is provided in an amount of 0.1 to 50 mg / kg body weight and per day.

16. Use according to one of the preceding claims, characterized in that the receptor antagonist in a preparation intended for administration or in a medication intended for administration in one Amount of 1 to 75% by weight, preferably 5 to 50% by weight, preferably 5 to 25% by weight, is contained.

17. A method for the treatment of disorders or diseases of the inner ear, characterized in that at least one vasopressin receptor antagonist or mixtures of such antagonists is administered in a suitable tolerable amount.

18. The method according to claim 17, characterized by at least one of the features of claims 2 to 16.

19. Pharmaceutical composition or medicament for the treatment of disorders or diseases of the inner ear, characterized in that it contains at least one vasopressin receptor antagonist or mixtures of such antagonists.

20. The composition or medicament according to claim 19, characterized by at least one of the features of

Claims 7 to 16.